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Development of Lc/Ms Techniques for Plant and Drug Metabolism Studies A 574 OULU 2011 A 574 UNIVERSITY OF OULU P.O.B. 7500 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATISUNIVERSITATIS OULUENSISOULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTAACTA SERIES EDITORS SCIENTIAESCIENTIAEA A RERUMRERUM Aleksanteri Petsalo NATURALIUMNATURALIUM ASCIENTIAE RERUM NATURALIUM Aleksanteri Petsalo Senior Assistant Jorma Arhippainen DEVELOPMENT OF BHUMANIORA LC/MS TECHNIQUES Lecturer Santeri Palviainen CTECHNICA FOR PLANT AND DRUG Professor Hannu Heusala METABOLISM STUDIES DMEDICA Professor Olli Vuolteenaho ESCIENTIAE RERUM SOCIALIUM Senior Researcher Eila Estola FSCRIPTA ACADEMICA Director Sinikka Eskelinen GOECONOMICA Professor Jari Juga EDITOR IN CHIEF Professor Olli Vuolteenaho PUBLICATIONS EDITOR Publications Editor Kirsti Nurkkala UNIVERSITY OF OULU, FACULTY OF SCIENCE, DEPARTMENT OF CHEMISTRY, ISBN 978-951-42-9440-2 (Paperback) FACULTY OF MEDICINE, ISBN 978-951-42-9441-9 (PDF) INSTITUTE OF BIOMEDICINE, ISSN 0355-3191 (Print) DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY ISSN 1796-220X (Online) ACTA UNIVERSITATIS OULUENSIS A Scientiae Rerum Naturalium 574 ALEKSANTERI PETSALO DEVELOPMENT OF LC/MS TECHNIQUES FOR PLANT AND DRUG METABOLISM STUDIES Academic dissertation to be presented with the assent of the Faculty of Science of the University of Oulu for public defence in Auditorium F100, Futura, Joensuu Campus, on 4 June 2011, at 2 p.m. UNIVERSITY OF OULU, OULU 2011 Copyright © 2011 Acta Univ. Oul. A 574, 2011 Supervised by Docent Ari Tolonen Docent Miia Turpeinen Reviewed by Professor Janne Jänis Docent Tiia Kuuranne ISBN 978-951-42-9440-2 (Paperback) ISBN 978-951-42-9441-9 (PDF) http://herkules.oulu.fi/isbn9789514294419/ ISSN 0355-3191 (Printed) ISSN 1796-220X (Online) http://herkules.oulu.fi/issn03553191/ Cover Design Raimo Ahonen JUVENES PRINT TAMPERE 2011 Petsalo, Aleksanteri, Development of LC/MS techniques for plant and drug metabolism studies. University of Oulu, Faculty of Science, Department of Chemistry, P.O. Box 3000, FI-90014 University of Oulu, Finland, Faculty of Medicine, Institute of Biomedicine, Department of Pharmacology and Toxicology, P.O. Box 5000, FI-90014 University of Oulu, Finland Acta Univ. Oul. A 574, 2011 Oulu, Finland Abstract Liquid chromatography (LC) combined with mass spectrometry (MS) is a powerful tool for qualitative and quantitative analytics of organic molecules from various matrices, and the use of this hyphenated technique is very common in bioanalytical laboratories. In this study, LC/MS methods and the required sample preparation applications were developed for plant flavonoid and drug metabolism studies. The main focus was in developing methods to be used during cytochrome P450 (CYP) -specific drug interaction studies. Traditional high performance liquid chromatography (HPLC) and new, more efficient and faster ultra-performance liquid chromatography (UPLC) were utilized together with time-of-flight (TOF) and triple quadrupole (QqQ) mass spectrometry. In the flavonoid study, collision-induced radical cleavage of flavonoid glycosides was tested and observed to be a suitable tool for the structure elucidation of the 15 flavonol glycosides extracted from the medicinal plant Rhodiola rosea. Ten of these glycosides were previously unreported in the plant. Several unreported in vivo bupropion metabolites were identified from human urine when developing the method for the new and more extensive in vitro and in vivo N-in-one interaction cocktail assays. The qualified analysis methods developed here enable faster analysis for the N- in-one cocktail assays, in turn enabling a more efficient screening of drugs that affect CYP- enzyme activities. In the case of the human in vitro cocktail assay, fourteen compounds were analyzed using a single LC/MS/MS run. The method has proven to be very reliable and has been used in several interaction studies utilizing different sample matrices. The in vivo cocktail assay that was developed enables totally non-invasive sample collection from the patients, the urine sample being sufficient for the UPLC/MS/MS analysis of all target compounds. The last part of the study consisted of developing a specific and very sensitive UPLC/MS/MS method for the analysis of one of the in vivo cocktail analytes, the antidiabetic drug repaglinide, from human placenta perfusates. Keywords: cytochrome P450 enzyme system, drug metabolism, flavonoids, liquid chromatography, mass spectrometry, urine analysis Petsalo, Aleksanteri, LC/MS-menetelmien kehittäminen kasvi- ja lääkeaineiden metabolian tutkimukseen. Oulun yliopisto, Luonnontieteellinen tiedekunta, Kemian laitos, PL 3000, 90014 Oulun yliopisto, Lääketieteellinen tiedekunta, Biolääketieteen laitos, Farmakologia ja toksikologia, PL 5000, 90014 Oulun yliopisto Acta Univ. Oul. A 574, 2011 Oulu Tiivistelmä Nestekromatografia (LC) yhdistettynä massaspektrometriaan (MS) on tehokas työväline kvalita- tiivisessa ja kvantitatiivisessa analytiikassa, ja tätä tekniikkaa käytetään erityisesti bioalan labo- ratorioissa. Tässä väitöskirjatyössä kehitettiin ja sovellettiin LC/MS- ja näytteenkäsittelymene- telmiä kasvien flavonoidimetabolian ja lääkeaineiden metaboliatuotteiden tutkimukseen keskit- tyen erityisesti sytokromi P450 (CYP) -entsyymispesifisten lääkeaineiden interaktiotutkimuk- siin tarvittaviin menetelmiin. Työssä hyödynnettiin perinteistä korkean erotuskyvyn nestekroma- tografiaa (HPLC) ja uutta, suorituskyvyltään vielä tehokkaampaa ja nopeampaa nestekromato- grafiaa (UPLC) yhdessä lentoaika- (TOF) ja kolmoiskvadrupolimassaspektrometrian (QqQ) kanssa. Tutkimustyön flavonoidimetaboliaan keskittyneessä osuudessa havaittiin törmäyksen aiheuttaman (CID) radikaalipilkkoutumisen soveltuvan lääkinnällisenä kasvina käytetystä ruusu- juuresta (Rhodiola rosea) uutettujen viidentoista flavonoliglykosidin rakennemääritykseen. Kymmentä näistä löydetyistä glykosideista ei oltu aiemmin raportoitu ruusujuuresta. Tutkimus- työn keskeisimpänä tavoitteena kehitettiin kvalifioidut LC/MS -analyysimenetelmät käytettäväk- si aikaisempaa kattavampien in vitro ja in vivo -olosuhteiden N-in-one -tyyppisten CYP-entsyy- mi-interaktiotutkimusten analyyttisenä työkaluna. Näitä analyysimenetelmiä kehitettäessä löy- dettiin ja tunnistettiin ihmisen virtsasta aiemmin raportoimattomia metaboliitteja CYP2B6 -ent- syymin malliaineena käytetyn bupropionin annostelun jälkeen. Kyseisten kehitettyjen analyysi- menetelmien avulla CYP-entsyymien toimintaan vaikuttavien lääkeaineiden tutkiminen on aiempaa nopeampaa ja antaa yhdellä kertaa samasta tutkimuksesta entistä laaja-alaisempaa tie- toa. In vitro -tutkimusta varten kehitetty LC/MS/MS -analyysimenetelmä on osoittautunut erit- täin käyttökelpoiseksi lukuisissa interaktiotutkimuksissa, ja in vivo -tutkimusta varten kehitetty UPLC/MS/MS -analyysimenetelmä mahdollistaa täysin ei-invasiivisen näytteenoton potilaista. Tutkimustyön viimeisessä vaiheessa kehitettiin erittäin herkkä ja spesifinen UPLC/MS/MS -ana- lyysimenetelmä CYP2C8-entsyymin toiminnan malliaineena käytetyn repaglinidin analysoimi- seksi koejärjestelystä, jossa tutkitaan yhdisteiden kulkeutumista raskausaikana äidin ja sikiön verenkierron välillä istukan kautta. Asiasanat: aineenvaihdunta, analyysimenetelmät, flavonoidit, lääkeaineet, massaspektrometria, nestekromatografia, sytokromit To my loved ones 8 Acknowledgements This work was carried out during the years 2005–2011. Most of the laboratory work was performed at Novamass facilities for which I am very grateful to Jouko Uusitalo (the founder of Novamass) and my supervisor Docent Ari Tolonen for giving me the opportunity to do my PhD studies there. I wish to express my warmest thanks to my supervisors, Docents Ari Tolonen and Miia Turpeinen, for introducing me to the fields of LC/MS and drug metabolism. Your guidance, knowledge and understanding have been a great support during these years. I am grateful to Professor Janne Jänis and Docent Tiia Kuuranne for their careful review of this thesis. Your constructive criticism and comments were valuable. I also want to thank Dr. Roy Goldblatt for revising the language of this thesis. I would like to thank all my co-authors, and especially professor Olavi Pelkonen for his whole-hearted contribution to our studies. I warmly thank all my colleagues and co-workers at Novamass and at the Structural Elucidation Chemistry Division of the Department of Chemistry for their collaboration. Particularly the laboratory staff is gratefully acknowledged. Finally, I would like to thank all my loved ones. I am deeply grateful to my parents for their never-ending love and support. I thank my brother for being nothing but himself. You have helped me in so many ways. I thank my sister and her family for the fun times we have had. I also want to thank PK for the everlasting support and believe in me. I sincerely thank my godparents and relatives for their financial support during these years. With your support I have been able to do things I like. My dear friends, you all are most warmly acknowledged. You make my journey worth of living and I can never express how much you all mean to me. And last but not least, I would like to thank my own coach for her love and understanding. Everything would be so different without you. Funding provided by the Orion-Farmos Research Foundation and Tauno Tönning Foundation is gratefully acknowledged. Joensuu, April 2011 Aleksanteri Petsalo 9 10 Abbreviations ADMET absorption, distribution, metabolism, excretion, toxicity ANR anthocyanidin reductase ANS anthocyanidin synthase APCI atmospheric pressure chemical ionization API atmospheric
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